Bruton's tyrosine kinase (Btk) is a non-receptor cytoplasmic tyrosine kinase belonging to the Tec family of kinases, members of which also include Tec, Itk, Txk, and Bmx. Most of these kinases are predominantly expressed in hematopoietic cells and play important roles in relaying signal transductions from cell surface receptors to direct cell development, differentiation, and other functions (Berg J J et al. Annual Review of Immunology, 2005; 23:549-600). Btk is critical for B-cell development, differentiation, maturation, and signaling (Mohamed A J et al. Immunological Reviews, 2009; 228:58-73). Loss-of-function mutations of Btk cause X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency in mice (Thomas J D et al. Science 1993; 261:355-358). Patients with XLA have normal pre-B cell populations in their bone marrow but these cells fail to mature and enter the circulation. Therefore, these patients essentially have no circulating B cells and are incapable of producing antibodies.
BTK plays pivotal roles in B-cell proliferation and activation mediated by B-cell receptor (BCR). Upon BCR activation, Btk is translocated to the plasma membrane where it is phosphorylated and subsequently initiates a cascade of signaling events including activation of phospholipase Cγ2 (PLCγ2) and eventually leading to calcium mobilization and transcriptional regulation involving nuclear factor kappa B (NF-κB) (Mohamed A J et al. Immunological Reviews 2009; 228:58-73). Because of the indispensable roles in BCR signaling pathway, it is believed that the kinase activity of Btk is critical for development and maintenance of a wide variety of B-cell malignancies, including chronic lymphocytic leukemia (CLL) and a number of non-Hodgkin's lymphoma (NHL) subtypes, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL) (Ponader S. et al. Blood 2012, 119:1182-1189; Honigberg L A et al. Proceedings of the National Academy of Sciences, 2010, 107:13075-13080). In addition, the role of B-cell in the pathogenesis of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and other immune disorders has been clinically demonstrated (Edwards J C et al. The New England Journal of Medicine, 2004, 350:2572-2581; Favas C et al. Nature Review Rheumatology, 2009, 5:711-716; Hauset S L et al. The New England Journal of Medicine, 2008, 358:676-688). Therefore, targeting Btk with small molecule inhibitors may provide therapeutic benefit for the treatment of B-cell malignancies and autoimmune diseases.